Investigational product: Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film coated 10 mg tablet with frequency of 1 tablet per day for 4 weeks

Investigational product: Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, and film coated tablet with frequency of 1 tablet per day for 4 weeks

Type 2 Diabetes

IMP oral tablet

Placebo oral tablet

CEDAR, Royal Surrey County Hospital

The Effect of a SGLT2 Inhibitor on Glucose Flux, Lipolysis and Exercise in Type 2 Diabetes

At visit 4 and visit 6, concentration of 3-hydroxybutyrate in plasma at baseline and during the visit (hourly for 8hr) will be measured by an enzymatic assay using PENTRA clinical chemistry analyser. The mean concentration of 3-hydroxybutyrate between 420-480 mins and the AUC of 3-hydroxybutyrate concentration time curve between 0-240 mins and 0-480 mins where the IMP was given at 0 mins in visits 4 and 6 will be calculated.The response will be compared following 4 weeks treatment with dapagliflozin versus placebo.

At visit 3 and visit 5, plasma NEFA concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma NEFA concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 3 and visit 5, plasma BOHB concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma BOHB concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 3 and visit 5, plasma ANP, noradrenaline and adrenaline measured by ELISA assays. Atrial natriuretic peptide, noradrenaline and adrenaline concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 3 and visit 5, plasma glucose concentration measured by an enzymatic assay on PENTRA, a clinical chemistry analyser and insulin and GH concentrations measured by respective radioimmune assays (RIA). Plasma glucose, insulin and growth hormone concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and AUC (0-60 minutes)will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 3 and visit 5, ECG taken at rest and during exercise will be compared following 4-weeks dapagliflozin versus placebo

At visit 3 and visit 5, blood pressure (BP) and heart rate taken at rest and during exercise. BP, HR and Rate Pressure Product (RPP=HR*SBP) will be measured at 0 minutes and at the end of each level of activity will be compared following 4-weeks dapagliflozin versus placebo

At visit 3 and visit 5, volumes of inhaled and expired air measured by a Cardio2 Med Graphics breath analyser, (VO2 and VCO2) taken at rest and at the end of each level of activity will allow calculation of carbohydrate and fat oxidation using established mathematical formula. These will be compared following 4-weeks dapagliflozin versus placebo

At visit 3 and visit 5, whole blood capillary lactate concentration measured by single use test strips (lactate Pro) containing an enzyme coated electrode using a lactate analyser (Lactate Pro) in response to exercise at the end of each exercise activity level will be analysed following 4 weeks treatment with dapagliflozin versus Placebo.

At visit 4 and visit 6, plasma glucose enrichment will be measured at basal and in in the last 30 minutes of 2H2-glucose infusion (450-480 min). Enrichment of 2H2glucose in plasma glucose will be measured using gas chromatography mass spectroscopy. Glucose production rate and MCR will be calculated from glucose enrichment data using standard isotope dilution equations. Glucose uptake will be determined by subtracting the rate of glucose excretion from the rate of glucose disappearance. Glucose concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes)

At visit 4 and visit 6, plasma glycerol enrichment will be measured at basal and in in the last 30 minutes of 2H5-glycerol infusion (450-480 min). Glycerol production rate and MCR will be calculated from glycerol enrichment data using standard isotope dilution equations.

At visit 4 and visit 6, following Folch extraction of the lipid moiety from plasma enrichment of 13C palmitate in NEFA and TAG pool will be measured by GCMS. The isotopic data for [13C] palmitate will be used to calculate the tracer concentration of [13C] palmitate in NEFA and TAG pool. • TAG concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. • The tracer concentration of [13C] palmitate in NEFA and TAG pool, will be measured as (AUC 0-240) minutes and AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes.

At visit 4 and visit 6, perchloric acid treated plasma from the studies will be used to extract BOHB and the enrichment of 13C BOHB will be measured by GCMS. The isotopic data for 3-hydroxybutyrate will be used to calculate the relative partitioning of systemic plasma NEFA into [13C] 3-hydroxybutyrate as the ratio of [13C] 3-hydroxybutyrate to [13C] palmitate (in NEFA and TAG pool) in the plasma, where [13C] is expressed in micromol/L. The ratio of [13C] 3-hydroxybutyrate to [13C] palmitate (in TAG pool) in the plasma will be calculated, where [13C] is expressed in micromol/l measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes.

At visit 4 and visit 6, the concentration of Glucagon, insulin and cortisol will be measured by RIA. Ratio of glucagon to insulin concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 4 and visit 6, the cardiac output responses investigated using Echocardiogram will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 4 and visit 6, aortic pulse wave velocity (m/s) will be measured by Vicorder between a cuff placed on the leg and around the neck. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.

At visit 4 and visit 6, targeted metabolomics will be used to measure 188 species from the metabolome including 40 species of acyl carnitines at 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.

University of Leicester

Royal Surrey County Hospital NHS Foundation Trust

AstraZeneca

The study is a randomised double blind placebo control cross over trial. with 4-weeks washout period.

Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, and film coated tablet

Age Related Macular Degeneration

Reading of numbers or letters from a monitor

Colour Contrast Sensitivity

Aston University

Colour Contrast Sensitivity for the Early Detection of Wet Age-related Macular Degereration (CEDAR)

Evaluation of Multiple Assessment Modalities for the Detection and Characterisation of the Preclinical, Pre-symptomatic Stage of Neovascular Age-related Macular Degeneration

The Dunhill Medical Trust

Chronic Heart Failure

To conduct the exercise to the inspiratory muscles was used for IMT Threshold ® device (Threshold Inspiratory Muscle Trainer, HealthScan Products Inc., Cedar Grove, New Jersey) is one of the most used for training of inspiratory muscles in patients with several pathologies such as ICC.Threshold ® has been engaged in the patient's mouth by a mouthpiece, with the nose occluded by a nose clip. The exercise time was 3 minutes. During this period, participants were encouraged to only breathe through the mouth and maintain a respiratory rate between 12 and 16ipm. The exercise would be stopped if HR increased more than 20% and / or SpO2 < 88%.

inspiratory muscle exercise

Equal to the group with chronic heart failure.

Universidade Federal de Pernamabuco

Regional Distribution of Ventilation in Patients With Chronic Heart Failure

The POE (BTS Bioengineering, Italy) measures the volume changes of thoracoabdominal system through placement of 89 markers formed by hemiesferas covered with retro-reflective paper, taking the place of each of these hemiesferas determined by anatomical landmarks in anterior and posterior thorax and abdomen.

To assess the functional capacity test was used for 6-minute walk (6MWT) according to the protocol established by the American Thoracic Society (ATS). Before the test parameters were assessed resting blood pressure (BP), Heart Rate (HR), Oxygen Saturation (SpO2 - pulse oximetry portable Onix 9500), Respiratory Frequency (RF) and dyspnea scale (scale Borg).

Armèle de Fátima Dornelas de Andrade

Universidade Federal de Pernambuco

Bravelle
Bravelle(follicle stimulating hormone) : One dose of 6 amps of Bravelle given at the same time as HCG ovulation trigger.

Bravelle

Saline
Saline ( placebo) : 1 cc of Normal Saline (placebo) given at the same time as HCG ovulation trigger.

Placebo

Total

Sex: Female, Male

Region of Enrollment

Number of normally fertilized oocytes (2PNs) divided by the total number of oocytes collected (i.e., not just the number of inseminated MII oocytes). This accounted for the possibility of both an enhanced oocyte maturation and improved fertilization of the mature oocytes. This also permitted inclusion of both IVF and intracytoplasmic sperm injection (ICSI) cycles in a way that allowed for evaluation of collective fertilization rates (i.e., typically, the denominator in IVF in calculating fertilization rate is all eggs collected, but in ICSI it is calculated using only the number of MII oocytes injected).

Mean Fertilization Proportion (2PN/Oocytes Collected)

Likelihood of obtaining an oocyte from a single mature-sized follicle on each ovary.

Mature Oocyte Recovery Rate

Fetal heart motion by transvaginal ultrasound

Pregnancy

Overall Study

Mitchell P. Rosen, MD

Infertility

One dose of 6 amps of Bravelle given at the same time as HCG ovulation trigger.

Bravelle(follicle stimulating hormone)

1 cc of Normal Saline (placebo) given at the same time as HCG ovulation trigger.

cedrela balansae/atrophy

The Effect of a SGLT2 Inhibitor on Glucose Flux, Lipolysis and Exercise in Type 2 Diabetes

Colour Contrast Sensitivity for the Early Detection of Wet Age-related Macular Degereration (CEDAR)

Regional Distribution of Ventilation in Patients With Chronic Heart Failure

Concomitant Administration of FSH With HCG Improves Oocyte Maturation and Quality Double -Blinded Randomized Trial

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